A growing body of literature suggests that stress-related conditions such as post-traumatic stress disorder (PTSD) are associated with chronically increased activity of CNS circuits the utilize corticotropin-releasing factor (CRF), a neuropeptide involved in mediating the neuroendocrine, immune, autonomic, and behavioral responses to stress. The development of CRF-, receptor antagonists as novel therapeutic agents has been a focus of intense investigation for the treatment of mood and anxiety disorders, though no such compounds are currently FDA-approved, and no clinical trial with CRF! receptor antagonists has ever been conducted in patients with PTSD. During the last funding period, the Mount Sinai School of Medicine (MSSM) and the NIMH intramural research program, in collaboration with GlaxoSmithKline, initiated a Phase II clinical trial of a neurokinin-1 antagonist in PTSD. In the current proposal, we will conduct a 2-site (MSSM and Emory University School of Medicine) Phase II clinical trial of a novel CRF, receptor antagonist in 154 adult patients with civilian (non-combat) PTSD with the following aims: Specific Aims: (1) To test the acute efficacy and safety of a CRF! receptor antagonist, GSK008, in PTSD, in a 12-week, randomized, double-blind, placebo-controlled, fixed dose, parallel-arm design. (2) To examine primary outcome measures, which are reductions in Clinician Administered PTSD Scale (CAPS) score at 12 weeks, and secondary outcomes, which are percentage of responders determined by CAPS and reductions in depressive symptoms. (3) As exploratory aims, we will investigate psychophysiological, neuroendocrine, genetic, and cognitive and functional aspects of change following treatment to identify baseline (pretreatment) moderating variables that offer predictive value for response to GSK008 in PTSD, and investigate correlates of response. Significance. Despite its prevalence and morbidity, there are only 2 FDA-approved medications for PTSD. neither of which were studied based on any pathophysiological rationale. Given the modest effect sizes for existing agents, the discovery of safe and effective new treatments for PTSD is a public health imperative with broad implications for other stress-related disorders. In addition, the investigative team is uniquely poised to explore several surrogate biomarkers during the trial, which will enable future studies specifically directed to detection of possible moderators of treatment.